Project Summary Despite advances in surgical and therapeutic approaches, veterans have a 4-times higher risk for developing prostate cancer compared with non-veterans. Therefore novel strategies to prevent or delay development and progression of clinically significant disease in this population are critical for successful management of prostate cancer. The goal of this VA-Merit proposal is to develop a safe and effective strategy for management of clinically significant prostate cancer using a novel bark extract namely NexrutineR. This is based on strong published and preliminary unpublished studies from our laboratory demonstrating (i) NexrutineR intervention inhibits early stage tumor development in a preclinical animal model that develops prostate cancer akin to humans; (ii) NexrutineR treatment reduces Akt activation, transcriptional activity of CREB and NF:B and expression of antiapoptotic protein FLIP in prostate cancer cells and (iii) overexpression of myristoylated Akt protects prostate cancer cells from NexrutineR - induced growth inhibition. Preliminary results also show that reduction in the protein levels of pmTOR (2448) and pAkt (473) within 2h of NexrutineR; implicating a role for Akt/mTOR signaling in NexrutineR-induced biological activities. Despite such promising results, the precise role of mTORC2/Akt signaling and signaling pathways downstream of Akt, including CREB in NexrutineR-induced inhibition of cell proliferation/survival and induction of apoptosis remains to be established. Further it is not known whether NexrutineR is effective only in preventing early stage prostate tumors or it will be effective in other stages of prostate cancer. In addition, published studies from our laboratory and other investigators demonstrate a good correlation between expression of FLIP, CREB, Akt, NF:B and tumor grade in human prostate cancer patients. This data supports the concept that a substantial number of VA patients with high grade prostate cancer may benefit from strategies targeting FLIP, CREB, Akt, NF:B signaling or pathways that activate these molecules. To date no studies have examined the potential for combined targeting of these critical signaling pathways for prostate cancer management. We have designed experiments to fill these critical gaps using state-of-the-art methodologies including magnetic resonance imaging (MRI) for monitoring tumor development in animals, siRNA approaches, ChIP analysis in addition to standard molecular and biochemical approaches. Although multicomponent approach has been successfully applied in the treatment of diseases such as tuberculosis, AIDS and leukemia, such strategies have not been exploited fully for prostate cancer management. Therefore our approach targeting mTORC2/Akt/mTORC1 and Akt/NF:B- mediated signaling pathways simultaneously that play a critical role in prostate cancer progression while using a safe and cost-effective herbal supplement is novel and innovative. Results from these studies will likely provide mechanistic data and a detailed preclinical evaluation, setting the stage for the clinical assessment of NexrutineR against prostate cancer in VA patients.